The last documented case of smallpox occurred in 1977. Now a deadly kin of the virus is spreading out of the forest and into villages. by Wendy Orent

On September 1, 1970, a 9-month-old boy was brought to a hospital in Basankusu, a small town in the northwest of what is now called the Congo. The baby was covered with a horrible rash--large, hard, painful pustules that radiated out toward the face and the extremities. It looked just like smallpox, a virus that had supposedly been all but eradicated from the face of the Earth.

The doctors in Basankusu took samples, which eventually ended up in the hands of renowned Soviet virologist Svetlana Marrenikova. She grew the virus and inoculated it into a rabbit skin, where it produced a lesion she'd seen before, but never on a human. This was not smallpox but monkeypox, a disease first identified in 1958, when it was found spreading among Asian and African monkeys that had been captured for laboratory research.

Four cases in Liberia soon followed, and other reports of the disease began trickling in. Because smallpox was so rare, doctors could more easily diagnose monkeypox, which had apparently infected forest-dwelling Africans for centuries but was completely unknown to most of the world. Unlike smallpox, one of the most virulent and highly contagious human diseases, monkeypox did not easily spread from person to person. Most victims were children who had caught and eaten small animals from the forest, including monkeys, squirrels, and rats.

As investigators learned from outbreaks during the next 20 years, African monkeypox, like smallpox, could kill as many as one of every 10 persons infected. In a World Health Organization study carried out from 1981 to 1986, investigators identified 338 monkeypox cases in Zaire (now the Congo) but concluded that it wasn't a major problem. For one thing, the disease had relatively few victims in a country haunted by malaria, tuberculosis, sleeping sickness, and AIDS. It also did not spread very quickly and was rarely transmitted through human contact.

But that was before anyone thought much about the monkeypox virus changing. New outbreaks of the disease indicate that it could be breaking free of its natural confines and spreading from person to person. If this scenario continues and monkeypox manages to spread from the forests of Africa into the world's major cities, it could become a major threat. Although old-fashioned smallpox vaccinations also immunize against monkeypox, few children have been inoculated since the 1970s, thanks to the World Health Organization's successful efforts to eradicate the disease. There are precious few stocks of vaccine anywhere, and no pharmaceutical firm has any plans to begin production. Ironically, just as scientists and governments are debating whether or not to destroy the last few vials of the smallpox virus, a hidden, scarcely known avatar may be rising in its place.

In 1996, civil unrest engulfed the Congo. A rebel army seized power and installed Laurent Kabila as head of state. In the province of Kasai Oriental, forest-dwelling Batetela peoples, hard-pressed by armies passing back and forth across the region, were forced to rely more on hunting and gathering for subsistence.

The Batetela lived in leaf-roofed huts built on the edge of the forest. Their children foraged there for squirrels, rats, and voles. When they were lucky, they caught the occasional monkey.

Before long, some of the local children became very ill--monkeypox again. But this time, a new and troubling characteristic had emerged.

Two traits are crucial to determining the severity of infectious threats: virulence and transmissibility. The virulence of this outbreak of monkeypox, the percentage of its victims dying, didn't seem to be increasing. But transmissibility, how the virus spreads, was a different matter. In previous outbreaks, human contact appeared to have spread only about one-fourth of the cases of monkeypox. Most cases came from trapping and skinning an infected animal. Reports from three separate missions conducted by the World Health Organization over the past three years indicate that the overwhelming majority--at least two-thirds--of the cases are now originating from person-to-person contact.

At last count, 511 cases had been diagnosed since the 1996 outbreak. But the disease continues to spread, and no one can be certain at what rate, given the state of the war-ravaged Congolese health care system. As of January, areas that still had contact with the outside world were reporting an average of one new case a day.

Ultimately some scientists fear that monkeypox could kill a lot more people than more horrifying viruses like Ebola or Marburg or hantavirus. "Most of the emerging diseases that attract media attention--Ebola, hantavirus, and the like--probably pose little threat of causing large-scale, runaway epidemics," says evolutionary biologist Paul Ewald of Amherst College, in Massachusetts. "They don't have the necessary mix of virulence and transmission characteristics. Not so with monkeypox. It causes damaging infections, grows productively in humans, is transmissible from person to person, and is durable in the external environment. In short, it has the right starting material for making a very nasty human pathogen."

Monkeypox, like smallpox, belongs to the family of orthopox viruses (see below). They are both encoded in DNA, and DNA viruses--unlike RNA viruses such as HIV and influenza--are not noted for their rapid mutability. But that doesn't mean they don't evolve. Under the right conditions, natural selection may allow survival of those strains best suited to infect humans.

To understand how a virus like monkeypox can spread through the entire world, consider the scenario that may have given rise to smallpox. For most of prehistoric times, people lived in small groups, subsisting on hunting and gathering or, later, slash-and-burn horticulture. There must have been the occasional infection, the occasional death, from a poxvirus, be it monkeypox, cowpox, or some ancestral virus that preceded them all. People may have contracted the virus the way Batetela children do now, catching and skinning infected animals. (The virus in animals' sores slipped into cracks in the children's hands, causing infections that spread to the throat and skin.) But even if the virus then swept through the whole tribe, the groups were far too small and dispersed for it to get a foothold. One, two, or 10 fell ill; then the infection burned out, not renewed again until someone somewhere else caught another infected animal.

But with the development of agriculture and the beginnings of settlements, it's easy to imagine the virus changing. Once a virus cropped up in a large population, it could spread more easily. There could have been accidents in copying viral dna that introduced mutations, or different viral strains could have recombined in a cell, forming a new variant. In any case, the strains best adapted to outwitting the human immune system survived. And those variants better adapted to spreading among the population would have survived best of all. Thus a virus introduced into a large population can be expected to rapidly develop greater transmissibility. According to one estimate, sustained transmission could occur if the virus were introduced into a population of 200,000 or more.

The same process could happen with monkeypox. Sergey Shchelkunov, a molecular biologist at Vector Laboratories in Novosibirsk, Siberia, who has worked on sequencing both smallpox and monkeypox strains, believes one must understand the relationship between the two to understand monkeypox's global threat. Shchelkunov argues that smallpox evolved from the ancestral monkeypox virus several millennia ago through a series of deletion mutations. Moreover, he thinks it's possible for a series of such mutations to transform existing monkeypox into a virus better adapted to humans. In other words, monkeypox could be changing again in ways that reenact the emergence of smallpox.

Although there's no scientific consensus on whether and how much monkeypox is changing, John W. Huggins of the U.S. Army Medical Research Institute of Infectious Diseases is worried about the increase in transmissibility. And he's been working on finding a cure.

Huggins was on the third team the World Health Organization sent out to study the present outbreak in the Congo. He works in a featureless building on the stark grounds of Fort Detrick, Maryland, in laboratories made famous by Richard Preston in his book The Hot Zone. The fort has long been a center for study of biological warfare defense. It features a biocontainment ward for those infected with lethal contagious diseases, and it has high-containment BL3 and BL4 laboratories for work on the most dangerous viruses for which no vaccine exists. Huggins is intimately familiar with such work.

Huggins's office is bright with posters and art brought from research ventures to the difficult places on Earth. He is a rather abrupt, sturdy middle-aged man with a good-humored laugh. He and his team headed off to the Congo partly to complete the work of preceding World Health Organization research teams, collecting serum samples from active cases of monkeypox and attempting a close study of the disease. They, like their predecessors, could not complete the work because of the war. Huggins barely made it out, grabbing a seat on the last commercial airline flight to Europe.

Huggins says the samples he gathered reveal two new traits not present in the monkeypox strain of 1976. The first is syncytia, in which infected cells tend to fuse together into cells with many nuclei. He also found differences in monoclonal antibody-binding patterns, a clue that the strains he found are distinct from the samples taken in the 1970s. Nevertheless, says virologist Joseph Esposito of the Centers for Disease Control and Prevention (CDC), Huggins's observations don't tell us whether the disease is growing more transmissible or more virulent. CDC virologist John Stewart, a member of the 1997 expedition to the Congo, is not familiar with Huggins's analyses but, like Esposito, he is not worried about monkeypox: "I don't think that our studies show anything to indicate that monkeypox is changing significantly." He attributes the increased incidence of the disease to the greater vulnerability of a younger, non-vaccinated population: Smallpox vaccinations, halted in the region in 1982, confer at least 85 percent immunity to monkeypox, although that immunity wanes over time.

The death rate from monkeypox is also in dispute. Esposito says the death rate for those infected in recent outbreaks is much lower than 10 percent. Huggins insists that there are pockets of infection where monkeypox is killing 10 percent of those it infects. More important is the question of whether monkeypox could become more virulent. If what happened with smallpox is any indication, it's certainly a possibility.

The smallpox that swept through Asia's cities in the 1960s was about four times as deadly as the African strain, probably because of the size and density of its host populations. In regions like Bangladesh, for example, where people live in tightly packed warrens, viruses can race through a city like wildfire. The most virulent strains would not pay a prohibitive evolutionary price by felling their hosts quickly. There is always another host, and another and another after that. Under crowded urban conditions, natural selection would favor the rapid evolution of extreme virulence. The smallpox strain the Soviets used to create a biological weapon was culled from a virulent outbreak that swept through cities in India in 1967.

In African villages, people don't live in crowded quarters. And the villages that Huggins visited were often separated by some distance. A virus could burn through a village and have nowhere to go. But there is a war in the Congo. The movement of troops and chaotic wartime living conditions can be very good for viruses.

Without more hard data, no one knows how much change monkeypox is undergoing. Huggins is not wasting time wondering. "I don't think like an evolutionary biologist," he says. "I just want to find a drug for these bugs and kill them." And perhaps he has. In preliminary tests conducted at the CDC, Huggins found that cidofovir, a drug originally developed to treat a viral infection in AIDS patients, appears to inhibit the replication of both monkeypox and smallpox. When he was in the Congo, he tried to set up a protocol for testing cidofovir on patients but had to abandon it. "You can't even contemplate setting up clinical trials without a stable government and a stable health care system," he says.

Civil war still rages in the Congo. Health conditions are getting worse. Marburg fever, a viral hemorrhagic disease that could be related to Ebola, has broken out in the country's mining region and may be spreading. Murders of civilians, theft and destruction of hospital equipment, and commandeering of jeeps and boats by government military and rebel forces have become commonplace, explains physician Paul Law of Johns Hopkins, codirector of the Sankuru River Health Project in the Congo. Huggins, meanwhile, has promised his wife and children that he won't fly into any more war zones.

All anyone can assume for now is that as long as monkeypox stays in the rain forest villages of the Congo or Sierra Leone and Liberia, where it has also been seen, it won't develop into a major threat. But all of these areas are war zones. Soldiers, from rebel and government factions alike, have cut a brutal path through the infected zone in the Congo. Both soldiers and refugees are on the move.

No one wants to think about what could happen to monkeypox in the large, crowded city of Kinshasa. Plagues & Poxes

It is one of the ironies of smallpox eradication that we never learned how smallpox kills. What we do know is that smallpox and its kin, monkeypox, belong to the orthopox family of viruses, which has entangled itself with rodents, cows, horses, buffalo, camels, monkeys, apes, and humans. Shaped like a brick and surrounded by a durable coat of fats and proteins, the orthopox virus is the largest of all animal viruses--just big enough to make out under a powerful light microscope. After it infects the organism, penetrating the animal's cells and multiplying in the cells of the spleen, bone marrow, and lymph glands, the virus releases its particles into the bloodstream. The virus travels to the deepest layer of the skin, then works its way up, producing the characteristic hard, painful, pus-filled lesions. Some researchers think smallpox victims were overwhelmed by a toxic immune response. But others, like John W. Huggins of the U.S. Army Medical Research Institute of Infectious Diseases, think smallpox victims died just as they do in more than 90 percent of monkeypox deaths--from pneumonia.

Smallpox is not only brutal, but hardy, too. A sample stored at room temperature may remain infectious for years. Smallpox and its kin are what biologist Paul Ewald calls "sit-and-wait pathogens"--infectious agents sturdy enough to linger on surfaces or in the air until hosts happen by. The virus can be coughed into the air. And it can survive in the sheddings of virus from pustules. The 18th-century British commander Jeffrey Amherst recognized the virus's potential as a biological weapon. He recommended distributing blankets contaminated with smallpox to Native Americans. Fighting the Pox

There are two legal stores of smallpox, one held at the Centers for Disease Control and Prevention in Atlanta, Georgia, the other at the Vector Laboratories in Novosibirsk, Siberia. For the past eight years, scientists and government officials have argued over whether to destroy these stocks. But American intelligence has known since 1991 that smallpox was cultivated in the Soviet Union for use in bioterrorism, and later reports place the virus in North Korea as well. Few people involved in the public debate over the future of smallpox had access to this information--and those who did weren't talking. But the proliferation of smallpox has become public knowledge since last year, when a high-level Russian defector, Ken Alibek, began speaking openly. The administration is now taking the threat of smallpox very seriously.

In March, a report prepared by the Institute of Medicine, a branch of the National Academy of Sciences, found that the most compelling reason to retain the much-disputed legitimate stocks of smallpox is the need to develop antiviral agents against it. Although a milder kind of smallpox--the vaccinia virus--has worked for more than 200 years to immunize people against the disease, it is no longer enough. The world has changed since smallpox was eradicated in 1980. The explosion of hiv infections has left people with immune systems so weak that a smallpox vaccine to protect against a bioterrorist attack--or monkeypox--could kill them. Antiviral drugs, however, can be used on anyone, regardless of hiv status.

John W. Huggins of the U.S. Army Medical Research Institute of Infectious Diseases is working with a drug, cidofovir, that holds promise. Originally developed to treat a viral infection that can blind aids patients, cidofovir inhibits an enzyme the virus needs to reproduce. If the drug works as well against monkeypox in humans as it does in monkeys, it may also be used to treat smallpox effectively--perhaps even more effectively, says Huggins, because a single difference in an amino acid in smallpox makes it more sensitive to the drug.

Still, there are problems with giving patients cidofovir. It can harm the kidneys, and it must be given intravenously.

Better drugs, including an oral form of cidofovir, are still in development. In May, the Clinton administration recommended keeping smallpox stocks because of the need for better antiviral drugs--a decision endorsed unanimously by the World Health Assembly.